Origin of the stimulation of food intake by oral administration of enkephalinase inhibitors in sheep

The influence of two enkephalinase inhibitors (thiorphan and acetorphan) orally, parenterally and centrally administered on food intake was tested in hay-fed ewes. When orally administered at a dose of 1 mg/kg, acetorphan, but not thiorphan, produced a biphasic increase in food intake corresponding to a 17.0% increase of daily food intake. Similarly thiorphan (0.1 mg X kg-1) IV administered increased by 19.3% the daily food intake; in contrast acetorphan IV administered produced a early (0-2 h) decrease followed by a late increase in hay consumption without significant (P greater than 0.05) change in the daily food intake. When ICV administered (10 micrograms X kg-1) thiorphan but not acetorphan at the same dose depressed the early (0-2 h) and daily food intake by 43.2% and 25.4% respectively. Pretreatment with naltrexone (0.1 mg X kg-1 IV) blocked the increased food intake induced by oral acetorphan or IV acetorphan and thiorphan but did not affect the anorectic effects of ICV thiorphan. We conclude that enkephalinase inhibitors like thiorphan and acetorphan increase daily food intake in sheep probably by increasing enkephalin levels in peripheral tissues.     

Calcitonin—C.N.S. action to control the pattern of intestinal motility in rats

Synthetic calcitonin injected into the lateral ventricles (ICV) of rats at picomolar concentration restores the “fasted” motility pattern of the small intestine in fed rats at doses as low as 0.083 picomoles. This effect which appeared in less than 5 min and persisted at least 2 hours for 0.83 picomole, was blocked by a previous intraventricular administration of 10 μg of calcium gluconate. At 0.83 picomole ICV, calcitonin also suppressed the disruption of the “fasted” pattern induced by intravenous infusion of Pentagastrin (6 μg·kg^?1·h^?1) but not that induced by insulin (0.5 U·kg^?1). These findings support the hypothesis that calcitonin acts centrally to control the pattern of intestinal motility by inhibiting the digestive influences responsible for the “fed” pattern. All of these peripheral influences are mediated by a Ca⁺⁺ sensitive central structure.     

Effects of corticotropin-releasing factor, corticotropin and cortisol on gastrointestinal motility in dogs

Gastrointestinal motor activity following intracerebroventricular (ICV) and intravenous (IV) administration of corticotropin releasing factor (CRF), corticotropin (ACTH) and cortisol was investigated in fasted dogs with strain-gauge transducers chronically implanted on the antrum and proximal jejunum. ICV but not IV administration of CRF (20 to 100 ng/kg) suppressed the gastric cyclic migrating motor complex (MMC) for 3 to 6 hours without affecting the jejunum. Similar disruptive effects on the gastric MMC were observed after ICV administration of ACTH (0.5 U/kg) or cortisol (0.1 micrograms/kg) but not after IV administration of 10 times higher doses. These results suggest that in dog CRF may be involved in the central control of the interdigestive gastric motility, these effects were not probably due to the release of ACTH and cortisol the other hormones of the pituitary adrenocortical system change the gastric motility when centrally administered through a possible feed-back mechanism affecting brain CRF level.     

Calcitonin gene-related peptide: Brain and spinal action on intestinal motility

The effects of intracerebroventricular (ICV) and intrathecal (IT) administration of calcitonin gene-related peptide (CGRP) on intestinal motility were examined in conscious rats chronically fitted with intraparietal electrodes in the duodeno-jejunum and a cannula in a cerebral lateral ventricle or catheter in the subarachnoid space. ICV administration of CGRP (0.5–10 μg) restores the fasted pattern of intestinal motility in fed rats in a dose-related manner. Intrathecal administration of CGRP or calcitonin also induces fasted pattern but after a 30 min delay. These effects persisted after transection of the spinal cord and no change in intestinal motility appeared after intravenous administration of CGRP at a dose effective when given IT. This study suggests that CGRP, as calcitonin, has a neuromodulatory role in the control of intestinal motility at both brain and spinal cord levels.     

Effects of intracerebroventricular administration of neurotensin,substance P and calcitonin on gastrointestinal motility in normal and vagotomized rats

The effects of intracerebroventricular (ICV) vs. intravenous (IV) injection of neurotensin, substance P and calcitonin on intestinal myoelectrical activity were examined in fed rats. ICV administered neurotensin and calcitonin restored the ‘fasted’ pattern of intestinal activity, i.e. the migrating myoelectric complex (MMC) at a dose as low as 12 and 0.2 pmol, respectively, whereas substance P only reduced significantly ($\text{P < 0.01}$) the duration of the postprandial pattern when injected ICV (48 pmol).Administered systemically at doses 100 times higher than the smallest active doses by the ICV route, calcitonin induced a fasted pattern, while neurotensin and substance P did not modify the fed pattern.The effects of ICV administration of neurotensin and calcitonin were abolished after vagotomy but the shortening effect of substance P on the duration of the postprandial pattern was still present.It is concluded that these three neuropeptides act centrally to control the pattern of intestinal motility in fed rats by shortening the ‘fed’ pattern for substance P and by restoring the MMC pattern for calcitonin and neurotensin, this last effect being mediated by the vagus.     

Effects of intracerebroventricular injections of thyrotropin releasing hormone on gastrointestinal propulsive motility in rats

The effect of intracerebroventricular (ICV) injections of thyrotropin releasing hormone (TRH) on the propulsive motility of the gastrointestinal tract was examined in rats. The distance travelled by charcoal meal through the small intestine, measured in terms of percentage of its total length, was recorded as the index of propulsive motility. The results were as follows: (1) The propulsive distance of charcoal meal was significantly reduced in a dose-dependent manner after ICV injections of TRH (1 microgram/10 microliters, 5 micrograms/10 microliters or 10 micrograms/10 microliters) (P less than 0.01-0.001) The effects were abolished by injection of atropine (5 micrograms/10 microliters ICV). (2) The gastrointestinal propulsive motility decreased markedly (P less than 0.01) after injection of a larger dose of TRH (50 micrograms/100 g) into the hypodermis. The effects were not completely blocked by subcutaneous injections of propranolol (5 mg/kg). (3) No effects (P greater than 0.05) were found on the inhibition of gastrointestinal propulsive motility after ICV injections of regitine (2.5 mg/kg im, 50 micrograms/50 microliters ICV) or propranolol (5 mg/kg im, 50 micrograms/50 microliters ICV). The results indicate that TRH has an inhibitory effect on the propulsive motility of gastrointestinal tract, which may be mediated via the non-adrenergic inhibitory nerve of the vagal nerves.     

Involvement of dopamine in the central effect of neurotensin on intestinal motility in rats

The effects of intracerebroventricular (ICV) administration of neurotensin (NT) before a meal on intestinal postprandial motility were examined in conscious rats chronically fitted with intraparietal Nichrome electrodes in the duodeno-jejunum. The effects were compared with those of two analogues, [D-Tyr¹¹]NT and [D-Trp¹¹]NT, resistant to degradation by brain peptidases. NT (10 μg ICV) delayed the occurrence of postprandial disruption of duodenal motility and blocked it on the jejunum. [D-Tyr¹¹]NT and [D-Trp¹¹]NT (1 μg ICV) elicited the same effects but at a ten-fold lower dose. NT administered peripherally just before a meal significantly lengthened the duration of the postprandial motor pattern. The central effect of NT on the fed pattern involved dopaminergic neurons as it was mimicked by dopamine, blocked by haloperidol and partly antagonized by either sulpiride or (+) SCH 23390. It is concluded that: 1) both D₁ and D₂ receptors are involved in the blocking effect of the postprandial disruption induced by central NT; 2) that [D-Tyr¹¹]NT and [D-Trp¹¹]NT are potent agonists at NT receptors in the brain.     

Action of endogenous prostaglandins on postprandial pyloric motility: a possible modulation by fats.

The involvement of endogenous prostaglandins (PGs) and the effect of exogenous PGs on the myoelectrical activity of the pylorus were examined for 6 hours after a meal in dogs chronically fitted with intraparietal electrodes on the gastroduodenal junction. The animals received either a standard meal or a fat meal which consisted of canned food added or not (standard meal) with arachis oil. The cyclooxygenase inhibitors, indomethacin (1 mg/kg) and piroxicam (0.2 mg/kg) given prior a fat meal significantly increased the frequency of pyloric spike bursts but did not modify the pyloric motility associated with a standard meal. Synthetic derivatives of PGE1 (misoprostol, 5-10 micrograms/kg) or PGE2 (enprostil 0.5-1 micrograms/kg) reduced the frequency of pyloric contractions after a fat but not a standard meal. It is suggested that both endogenous and exogenous prostaglandins may modulate postprandial pyloric motility when fats are present in sufficient amount into the meal.     

The effect of intestinal anaphylaxis on postprandial motility in the rat

We have previously utilized a rat animal model to demonstrate that challenge of fasted sensitized animals with antigenic food protein is associated with diarrhea and altered intestinal myoelectric and motor activities. In this paper we examine the effect of intestinal anaphylaxis on postprandial motility in the same animal model. Hooded Lister rats were sensitized (S) by intraperitoneal injection of 10 micrograms egg albumin (i.e., antigen (Ag) and compared with sham-sensitized controls (C). Seven days later, three bipolar jejunal electrodes and a jejunostomy tube, for motility recording and Ag administration, were implanted. On day 14, intestinal myoelectric and motor activities were measured in fed animals before and after intraluminal challenge with Ag (100 mg egg albumin/0.5 mL saline) or placebo (P; 0.5 mL saline). Specific immunoglobulin E serum titres were greater than or equal to 1:64 in S animals, while C animals showed no response. None of the C animals challenged with P or Ag and none of the S animals challenged with P defecated after challenge, but all the S animals challenged with Ag developed diarrhea (p less than 0.001). There was no disruption or alteration of the fed motility pattern in C animals challenged with P or Ag, or S animals challenged with P. In fed S animals challenged with Ag the fed motility pattern persisted, but there was a significant (p less than 0.05) increase in the number of high-amplitude aborally propagating clustered contractions, where the phasic contractile activity was superimposed on a sustained tonic elevation of intraluminal pressure lasting 5-10 s.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intestinal motility responses to insulin and glucagon in streptozotocin diabetic rats

Myoelectrical and mechanical activities were chronically recorded by use of nichrome electrodes and miniaturized strain-gage transducers sutured on the serosa of the antrum, the duodenum, and the jejunum. In a first experiment (n = 6 rats) the early (0-6 h) and late (greater than 4 days) effects of streptozotocin (65 mg/kg i.v.) was recorded. In addition, the effect of insulin (1-5 IU/kg) and glucagon (6-200 micrograms/kg) administered intravenously were studied separately each in groups of seven normal and streptozotocin-induced diabetic-fed and fasted rats. The results indicated that within the 30 min following streptozotocin administration there was a significant stimulation of the duodenal and jejunal motility lasting 46 +/- 8 min. When diabetes was established as shown by the basal blood glucose level obtained in those rats (2.30 +/- 0.84 g/L), a progressive decrease of the frequency of the migrating myoelectric complex was observed along with a disorganization of the regular spiking activity phases without disturbing the basal electrical rhythm. Comparing with the basal level, a significant increase in the gastrointestinal motility indexes (MI) appeared both in fasted (p less than 0.01) and fed (p less than 0.05) normal animals, 13.1 +/- 1.6 min after an i.v. injection of 1 IU/kg insulin. Motor effects of glucagon were related to the dose. When used at 25 microgram/kg a disorganization of the spiking activity was observed with a stimulation of the contractile activity in the jejunum. At higher dosages, i.e., 100 micrograms/kg, it induced an immediate and significant decrease of motility at any level tested and lasting up to 20 +/- 7 min. The motility responses to both hormones were lower in diabetic than in normal rats.     

Antagonistic effects of naloxone on CCK-octapeptide induced satiety and rumino-reticular hypomotility in sheep

Continuous intracerebroventricular (ICV) infusion of CCK-octapeptide (CCK8) was performed in ewes fitted with a permanent cannula into the lateral cerebral ventricle and Nichrome electrodes on the reticulum in order to record its electrical activity. In the first series of experiments, subsequently repeated in 12 h fasted animals, CCK8 was infused during the first hour of a 3 hour period of feeding at 2.5, 5 and 10 ng.kg-1.min-1. The same series of infusion were performed 20 min after ICV injection of 2.4 and 10 micrograms.kg-1 of naloxone. CCK8 reduced significantly in a dose related manner the food intake (r = 0.95; P less than 0.01) and the frequency of cyclic spike bursts associated to biphasic contractions of the reticulum observed during feeding (r = 0.89; P less than 0.01). At 5 and 10 ng.kg-1.min-1, the reduction of food intake reached 46.2 and 52.6% during the period of infusion; the basal and stimulated (feeding) frequency of reticular contractions were nearly halved. Previous ICV administration of naloxone (2.4 micrograms.kg-1) partially blocked the effects of CCK8 infusion on both food intake (72%) and reticular frequency (54% basal, 67% stimulated). The CCK8 induced effects on both food intake and frequency of reticular contraction were completely abolished after a previous 10 micrograms.kg-1 injection of naloxone. These results suggest that the central effects of CCK8 on feeding behavior and forestomach motility involve similar central structures and are mediated through opiate receptor structures.     

Reversal of the effects of centrally-administered morphine on colonic motility in dogs by the benzodiazepine receptor antagonist RO 15-1788

The effects of intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of morphine on jejunal and colonic motility were investigated in conscious dogs chronically prepared with strain gage transducers and compared to those of i.c.v. DAGO, a highly selective opiate mu agonist. Morphine i.v. (100 micrograms/kg) and i.c.v. (10 micrograms/kg) administered 3 hrs after a meal stimulated colonic motility for 3-5 hrs and induced a phase 3 on the jejunum, which appeared after a 15-60 min delay following i.c.v. administration. These effects were reproduced by DAGO administration at doses of 2 micrograms/kg i.v. and 0.2 micrograms/kg i.c.v. The effects of i.v., but not those of i.c.v., morphine and DAGO on jejunal and colonic motility were blocked by a previous administration of naloxone (100 micrograms/kg i.v.). The colonic stimulation but not the jejunal phase 3 induced by i.c.v. morphine and DAGO were blocked by RO 15-1788 (1 mg/kg i.v.), a selective benzodiazepine antagonist. The colonic stimulation induced by i.v. morphine or DAGO was not modify by i.v. RO 15-1788. It is concluded that i.c.v. administration of mu agonist involved benzodiazepine but not opiate receptors to stimulate colonic motility in dogs.     

Comparative study of the pulmonary effects of intravenous leukotrienes and other bronchoconstrictors in anaesthetized guinea pigs

Pulmonary responses to intravenous leukotrienes C4, D4 and E4 administered as a bolus injection and by continuous infusion were studied in anesthetized guinea pigs. LTD4, LTC4 and LTE4 (respective ED50 of 0.21 +/- .1, 0.64 +/- .2 and 2.0 +/- .1 microgram kg-1) produced dose-dependent increases in insufflation pressure when given as a bolus injection to anesthetized guinea pigs (Konzett-R?ssler). Bronchoconstriction was antagonized by FPL-55712 (50-200 micrograms kg-1), and indomethacin (50-200 micrograms kg-1) but was not significantly altered by mepyramine (1.0 mg kg-1), methysergide (0.1 mg kg-1), intal (10 mg kg-1) mepacrine (5 mg kg-1) or dexamethasone (10 mg kg-1). The beta adrenoceptor blocker, timolol (5 micrograms kg-1) produced a significantly greater potentiation of the responses to the leukotrienes than to arachidonic acid, histamine and acetylcholine. Responses to bolus injection of LTE4 but not LTD4 or LTC4 were partially antagonized by atropine (100 micrograms kg-1) and bilateral vagotomy. In experiments of a different design, continuous infusion of LTD4 and LTE4 (2.8-3.2 micrograms kg-1 min-1) into indomethacin-treated animals produced slowly developing increases in pulmonary resistance and decreases in compliance. The increase in resistance produced by LTE4 and LTD4 was partly reversed by intravenous FPL-55712 (1.0 mg kg-1) and atropine (100 micrograms kg-1) but was almost completely reversed by FPL-55712 (3 - 10 mg kg-1). These findings indicate that leukotrienes can produce bronchoconstriction in guinea pigs through cyclooxygenase-dependent and cyclooxygenase independent mechanisms both of which are blocked by FPL-55712. Cholinergic mechanisms are involved in the mediation of part of the response to bolus injection of LTE4 as well as a small part of the initial response to continuous infusion of LTD4 and LTE4. Intrinsic beta adrenoceptor activation serves to down modulate responses to the leukotrienes to a greater extent than responses to arachidonic acid, histamine and acetylcholine.     

A tetrapeptide isolated from hamster embryo with central opiate properties on gastrointestinal motility but not on pain perception

The effects of centrally administered kentsin (H-Thr-Pro-Arg-Lys-OH) on intestinal motility and on pain perception were investigated in rats chronically equipped with lateral ventricle catheters. Intestinal motility was recorded electromyographically from electrodes placed on the duodeno-jejunum; analgesia was evaluated by the hot-plate and tail-flick tests. Kentsin (4.0 ug/kg), injected intracerebroventricularly (ICV) 2 hours after the beginning of a meal, restores the "fasted" i.e. the migrating myoelectric complex of intestinal motility, while a 5 times higher dose administered subcutaneously was inactive. The ICV effect of kentsin was blocked by previous ICV administration of naloxone (400 ug/kg). In contrast, kentsin administered ICV (40 ug/kg) or SC (200 ug/kg) did not affect significantly (P greater than 0.05) the time latency in the two analgesic tests during 90 minutes after its administration and did not significantly modify the analgesic effects of (D5-Ala2, Met5) enkephalinamide. We conclude that kentsin when centrally administered acts on opiate receptors to alter gastrointestinal motility but without effects on pain perception.     

Brain CCKA receptors mediate the colonic motor response to feeding in dogs

The influence of central vs. peripheral administration of specific type A and type B CCK receptor antagonists (L364,718 and L365,260, respectively) on colonic motor hyperactivity induced by feeding and CCK8 was investigated in dogs with strain-gauge transducers implanted on the proximal and transverse colon. Intravenous injection of L364,718 (5 and 10 micrograms/kg) reduced by 26.2% and 80.1%, respectively, the 0-4-h postprandial increase in colonic motor index; at similar doses L365,260 had no effect. Intracerebroventricular administration of L364,718, at a dose (1 microgram/kg) not active by the IV route, significantly reduced (p less than 0.01) by 67.5% the feeding-induced colonic hyperactivity. In contrast, L365,260 (1-10 micrograms/kg ICV) injected was inactive. Increase in colonic motility produced by intravenous CCK8 infusion (1 microgram/kg/h) was suppressed by previous ICV and IV administration of L364,718 at doses of 1 and 10 micrograms/kg, respectively, while L365,260 was inactive at similar doses. It is concluded that CCK8 released after a meal is responsible for the postprandial increase in colonic motility and that these effects may be mediated through activation of central CCKA receptors.     

Influence of oxytocin on feeding behavior in the rat

Oxytocin, whether administered intraperitoneally (IP) (375-6,000 micrograms/kg) or intracerebroventricularly (ICV) (1-10 micrograms/rat), dose-dependently reduced food consumption and time spent eating and increased the latency to the first meal in rats fasted for 21 hr. Pretreatment with the oxytocin antagonist d(CH2)5Tyr(Me)-[Orn8]vasotocin (ICV 10 micrograms/rat) completely prevented the feeding inhibitory effect of an equal dose of ICV oxytocin, and per se increased food intake. Our data further support the hypothesis that oxytocin plays the role of neurotransmitter or neuromodulator in the CNS, and suggest that its involvement in a number of homeostatic systems may include appetite control.     

Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents

Objectives: Obestatin has been initially characterized as a new peptide derived from the ghrelin precursor, which suppresses food intake and inhibits the orexigenic and prokinetic actions of ghrelin when injected peripherally or centrally in lean mice. However, reproducing these data remains controversial. Reasons for the disparity may be the use of different doses, routes, and animal models. We aimed to investigate the effects of peripheral and intracisternal (IC) injection of obestatin on feeding, gastric motility, and blood glucose in rats as well as in diet‐induced obese (DIO) mice. Research Methods and Procedures: Food intake and gastric emptying of a semi‐liquid caloric meal were measured after intraperitoneal (IP) injection of obestatin in rats and DIO mice. Gastric phasic motility and blood glucose were monitored in urethane‐anesthetized rats after IC or intravenous (IV) injection of obestatin. Results: Obestatin injected intraperitoneally at doses ranging from 0.1 to 3 mg/kg influenced neither acute food intake nor gastric emptying in rats. Obestatin injected intravenously at 0.3 or 3 mg/kg and IC at 7.5 or 30 µg/rat modified neither fasted gastric phasic motility nor blood glucose levels, while ghrelin (30 µg/kg, IV) increased and vagotomy suppressed gastric motility, and an oligosomatostatin analog (3 µg/rat, IC) decreased blood glucose. Obestatin, injected intraperitoneally (0.3 mg/kg) in DIO mice, did not alter feeding response to a fast, while urocortin 1 (10 µg/kg, IP) induced a 73.3% inhibition at 2 hours. Discussion: Our data demonstrate that peripheral administration of obestatin did not modify food intake in rats or obese mice or gastric motor function in rats.     

Enhancement of colonic motor response to feeding by central endogenous opiates in the dog

The role of endogenous opiates in the colonic motor response to feeding has been investigated in four dogs chronically fitted with two strain gages on the proximal and distal colon and a cannula in cerebral lateral ventricle. A daily meal stimulated the colonic motility during 8-10 hrs. The colonic motility index was significantly higher during this period when an enkephalinase inhibitor, tiorphan, was intracerebroventricularly (i.c.v.) administered at a dose of 0.1 mg/kg before the meal. This effect was blocked by a previous i.c.v. administration of naltrexone (0.1 mg/kg) and reproduced by (D-Ala2, Met5) enkephalinamide (DALAMIDE) at a dose of 50 mg/kg. I.c.v. administration of tiorphan or DALAMIDE did not modify the colonic motility in dogs fasted for 48 hrs. The postprandial motility index remained unchanged after intravenous administration of tiorphan or DALAMIDE at the same dosages. These results provide evidence for a central control of the colonic motor response to feeding by endogenous enkephalins in dogs.     

Influence of centrally administered somatostatin and two related peptides on intestinal absorption of water and electrolytes in conscious dogs

The effects of intracerebroventricular (ICV) administration of somatostatin (SRIF) and two related peptides, anti SRIF and SMS 201-995, on jejunal fluxes of water, Na+ and K+ were investigated in dogs prepared with a Thiry-Vella (TV) loop. Intestinal transport in the TV loop and concomitant transit time were also measured during infusion (2 mg/min) of an isotonic electrolyte solution and phenol-red bolus injections. Basal net water absorption was reduced significantly (p less than 0.01) over periods of 2 to 5 hr and in a dose-related manner, with ICV administrations of SRIF (5 to 100 ng/kg); doses of SRIF, 5 to 25 times higher but administered IV, were inactive. Similar reductions in the net fluxes of water, Na+ and K+ were observed over 2 to 5 hr following ICV administration of a putative somatostatin antagonist and SMS 201-995 at doses of 100 ng/kg. Neither metoclopramide (1 mg/kg), phentolamine (0.1 mg/kg) nor methysergide (0.2 mg/kg) given IV were able to antagonize the effects of centrally administered SRIF (100 ng/kg) on intestinal fluxes. In contrast, the effects of SRIF were abolished completely by naloxone (0.2 mg/kg) but not methyl-naloxone (0.3 mg/kg) given systemically. It is concluded that somatostatin and the two related peptides act centrally to reduce jejunal absorption of water and electrolytes. The effects of SRIF appear to be related to opiate receptors, possible involving central nerve pathways which utilize opiate-like transmitters.     

Growth hormone response of bull calves to growth hormone-releasing factor

Three experiments were conducted to determine serum growth hormone (GH) response of bull calves (N = 4; 83 kg body wt) to iv injections and infusions of human pancreatic GH-releasing factor 1-40-OH (hpGRF). Peak GH responses to 0, 2.5, 10, and 40 micrograms hpGRF/100 kg body wt were 7 +/- 3, 8 +/- 3, 18 +/- 7, and 107 +/- 55 (mean peak height +/- SEM) ng/ml serum, respectively. Only the response to the 40-microgram dose was greater (P less than 0.05) than the 0-microgram dose. Concentrations of prolactin in serum were not affected by hpGRF treatment. In calves injected with hpGRF (20 micrograms/100 kg body wt) at 6-hr intervals for 48 hr, GH increased from a mean preinjection value of 3.1 ng/ml serum to a mean peak response value of 70 ng/ml serum. Differences in peak GH response between times of injection existed within individual calves (e.g., 10.5 ng/ml vs 184.5 ng/ml serum). Concentrations of GH in calves infused continuously with either 0 or 200 micrograms hpGRF/hr for 6 hr averaged 7.4 +/- 3 and 36.5 +/- 11 ng/ml serum, respectively (P less than 0.05). Concentrations of GH oscillated markedly in hpGRF-infused calves, but oscillations were asynchronous among calves. We conclude that GH response of bull calves to hpGRF is dose dependent and that repeated injections or continuous infusions of hpGRF elicit GH release, although magnitude of response varies considerably. We hypothesize that differences in GH response to hpGRF within and among calves, and pulsatile secretion in the face of hpGRF infusion may be related to the degree of synchrony among exogenous hpGRF and endogenous GRF and somatostatin.